Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans


The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity1. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ex vivo infection of explants of tumour and normal tissue from patients reveals tumour-selective JX-594 gene expression.
Figure 2: JX-594 is selectively delivered to, and amplified within, tumours after intravenous infusion.
Figure 3: Immunohistochemical staining reveals JX-594 infection and β-galactosidase expression in tumours.


  1. Kirn, D. H. & Thorne, S. H. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nature Rev. Cancer 9, 64–71 (2009)

    Article  CAS  Google Scholar 

  2. Parato, K. A., Senger, D., Forsyth, P. A. & Bell, J. C. Recent progress in the battle between oncolytic viruses and tumours. Nature Rev. Cancer 5, 965–976 (2005)

    Article  CAS  Google Scholar 

  3. Liu, T. C., Galanis, E. & Kirn, D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat. Clin. Pract. Oncol. 4, 101–117 (2007)

    Article  CAS  PubMed  Google Scholar 

  4. Vanderplasschen, A., Hollinshead, M. & Smith, G. L. Antibodies against vaccinia virus do not neutralize extracellular enveloped virus but prevent virus release from infected cells and comet formation. J. Gen. Virol. 78, 2041–2048 (1997)

    Article  CAS  PubMed  Google Scholar 

  5. Vanderplasschen, A., Mathew, E., Hollinshead, M., Sim, R. B. & Smith, G. L. Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope. Proc. Natl Acad. Sci. USA 95, 7544–7549 (1998)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wein, L. M., Wu, J. T. & Kirn, D. H. Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery. Cancer Res. 63, 1317–1324 (2003)

    CAS  PubMed  Google Scholar 

  7. Smith, G. L., Murphy, B. J. & Law, M. Vaccinia virus motility. Annu. Rev. Microbiol. 57, 323–342 (2003)

    Article  CAS  PubMed  Google Scholar 

  8. Katsafanas, G. C. & Moss, B. Vaccinia virus intermediate stage transcription is complemented by Ras-GTPase-activating protein SH3 domain-binding protein (G3BP) and cytoplasmic activation/proliferation-associated protein (p137) individually or as a heterodimer. J. Biol. Chem. 279, 52210–52217 (2004)

    Article  CAS  PubMed  Google Scholar 

  9. Yang, H. et al. Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. J. Clin. Invest. 115, 379–387 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000)

    Article  CAS  PubMed  Google Scholar 

  11. Mastrangelo, M. J. et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther. 6, 409–422 (1999)

    Article  CAS  PubMed  Google Scholar 

  12. Kim, J. H. et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol. Ther. 14, 361–370 (2006)

    Article  CAS  PubMed  Google Scholar 

  13. Buller, R. M., Smith, G. L., Cremer, K., Notkins, A. L. & Moss, B. Decreased virulence of recombinant vaccinia virus expression vectors is associated with a thymidine kinase-negative phenotype. Nature 317, 813–815 (1985)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Park, B. H. et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 9, 533–542 (2008)

    Article  CAS  PubMed  Google Scholar 

  15. Hovgaard, D., Mortensen, B. T., Schifter, S. & Nissen, N. I. Clinical pharmacokinetic studies of a human haemopoietic growth factor, GM-CSF. Eur. J. Clin. Invest. 22, 45–49 (1992)

    Article  CAS  PubMed  Google Scholar 

  16. Choi, H. et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J. Clin. Oncol. 25, 1753–1759 (2007)

    Article  PubMed  Google Scholar 

  17. Byrne, M. J. & Nowak, A. K. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann. Oncol. 15, 257–260 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Moss, B. Vaccinia virus: a tool for research and vaccine development. Science 252, 1662–1667 (1991)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Peng, K. W. et al. Intraperitoneal therapy of ovarian cancer using an engineered measles virus. Cancer Res. 62, 4656–4662 (2002)

    CAS  PubMed  Google Scholar 

  21. McCart, J. A. et al. Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2: molecular imaging after systemic delivery using 111In-pentetreotide. Mol. Ther. 10, 553–561 (2004)

    Article  CAS  PubMed  Google Scholar 

  22. Msaouel, P. et al. Noninvasive imaging and radiovirotherapy of prostate cancer using an oncolytic measles virus expressing the sodium iodide symporter. Mol. Ther. 17, 2041–2048 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. McCart, J. A. et al. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 61, 8751–8757 (2001)

    CAS  PubMed  Google Scholar 

  24. Thorne, S. H. et al. Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. J. Clin. Invest. 117, 3350–3358 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thorne, S. H. et al. Targeting localized immune suppression within the tumor through repeat cycles of immune cell-oncolytic virus combination therapy. Mol. Ther. 18, 1698–1705 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–386 (2000)

    CAS  PubMed  Google Scholar 

  27. Kulesh, D. A. et al. Smallpox and pan-orthopox virus detection by real-time 3′-minor groove binder TaqMan assays on the Roche LightCycler and the Cepheid Smart Cycler platforms. J. Clin. Microbiol. 42, 601–609 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst. 92, 205–216 (2000)

    Article  CAS  PubMed  Google Scholar 

  29. Choi, H. et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am. J. Roentgenol. 183, 1619–1628 (2004)

    Article  PubMed  Google Scholar 

  30. Myers, J. L. W. & Arnold, D. Research Design and Statistical Analysis. 2nd edn, 505–512 (Laurence Erlbaum, 2003)

    Book  Google Scholar 

Download references


Jennerex Inc. was involved in the study design, data monitoring, analysis and interpretation, and in writing and submission of the report for publication. Jennerex Inc. funded the clinical study. Translational work was supported by grants to J.B. from the Terry Fox Foundation and the Canadian Institute for Health Research (CIHR) and by grants to T.-H.H. from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A091047). N.D.S. is supported by a Vanier Scholarship. C.J.B. was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) studentship. L.E. is supported by Ontario Graduate Scholarships in Science and Technology (OGSST). F.L.B. is supported by a Canadian Institutes of Health Research/Small and Medium Enterprises (CIHR/SME) Collaborative Research Program Fellowship. A.F. and J.C.B. are supported by Ontario Institute for Cancer Research.

Author information

Authors and Affiliations



Study design: D.H.K. and J.C.B. Data analysis and study write-up: C.J.B., D.H.K., T.-H.H., A.M., R.P., A.P., T.R., J.C.B. and A.F. Enrolment and management of patients: J.B., D.J., J.S., A.R.H., L.Q.M.C. and J.N. Laboratory work: F.L.B., J.B., N.D.S., S.C., J.-E.J., L.E., Y.-S.L., K.P., J.S.D., M.D. and J.-S.D. C.J.B. and D.H.K. had access to all the data in the trial. C.J.B. and D.H.K. took the final decision to submit for publication.

Corresponding author

Correspondence to David H. Kirn.

Ethics declarations

Competing interests

C.J.B., J.B., A.M., A.P., T.R. and D.H.K. are employees of Jennerex Inc. and hold stock options in Jennerex Inc. T.-H.H. and J.C.B. consult for and hold stock options in Jennerex Inc. R.P., Y.-S.L. and M.D. consult for Jennerex Inc.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-4 with legends, a Supplementary Discussion and Supplementary References. (PDF 636 kb)

Supplementary Movie 1

This movie shows the 360° view of a colorectal carcinoma tumour in which vaccinia (JX-594) antigens were detected by immunohistochemistry. Green staining represents areas of tumour staining for vaccinia (JX-594). (MOV 1573 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Breitbach, C., Burke, J., Jonker, D. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing